Neonatal Dubin‐Johnson Syndrome with Severe Cholestasis: Effective Phenobarbital Therapy

Kimura, Akihiko; Ushijima, Kosuke; Kage, Masayoshi; Mahara, Reijiro; Tohma, Masahiko; Isobe, Takashi; Shibao, Kyoko; Tanaka, Noriaki; Fujisawa, Tomotsumi; Ono, Eiichiro; Yamashita, Fumio

doi:10.1111/j.1651-2227.1991.tb11867.x

Cited by 29 publications

(18 citation statements)

References 8 publications

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“…DJS is rarely diagnosed in the neonatal period and its presentation as severe cholestasis is uncommon in neonates (21)(22)(23)(24)(25)(26)(27)(28). There has been no report on long-term follow-up and genetic studies of DJS with a neonatal onset.…”

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confidence: 99%

Neonatal Dubin-Johnson Syndrome: Long-Term Follow-up and MRP2 Mutations Study

Lee

Chen

et al. 2006

Pediatr Res

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Neonatal Dubin-Johnson syndrome (DJS) is rarely diagnosed and mutational analysis of multidrug-resistance-associated protein 2 (MRP2) in such patients had not been reported. We aimed to investigate the possible correlations between genotype and phenotype of patients with DJS. Four cases of DJS, two diagnosed during the neonatal period and two diagnosed at adolescence, were followed for 5-20 y. Mutational analysis in the MRP2/ABCC2 gene was performed in all four cases. Biphasic pattern of jaundice attack was observed in one patient who was followed for 20 y, with jaundice subsiding before 1 y of age and recurring at adolescence. Six novel mutations in four patients were found, including deletions (2748del136, 3615del229, and Del3399-3400), and missense mutations (L441M and E1352Q) and nonsense mutation (Y1275X). The immunohistochemical staining in liver tissues from two patients with neonatal onset showed negative staining for MRP2. Reviewing previously reported cases, all patients diagnosed as DJS before 10 y of age have mutations involving one of the two ATP-binding cassettes (ABC) of the MRP2. This study suggests that long-term follow-up is indicated for neonatal DJS because of possible recurrence and/or second attacks of jaundice in later life, and that disruption of functionally important ABC domains in MRP2 may be related to the earlier onset of the disease. of chronic or intermittent conjugated hyperbilirubinemia, a defect in the excretion of anionic conjugate from the hepatocyte into the bile, delayed clearance of intravenous bromosulfophthalein (BSP), increased urinary excretion of coproporphyrin I, and hepatic histopathology of lysosomal accumulation of black pigment (1-3). Most patients are asymptomatic, although some patients presented with vague right-upper-quadrant abdominal pain, weakness, nausea, or vomiting. Physical examination is frequently normal or unremarkable. Jaundice is evident by the time of puberty in about half, and by the age of 20 in about two-thirds, of affected persons (1). Liver enzymes are usually within normal limits, although the bilirubin levels fluctuate (1).The molecular mechanism in DJS is impaired hepatobiliary excretion of anionic conjugate caused by the defects of MRP2 or cMOAT (4,5). The formal genetic name is ABCC2. MRP2 protein acts as an ATP-dependent export pump for anionic glutathione or glucuronate conjugate from hepatocyte into bile and is expressed at the apical/canalicular plasma membrane of hepatocyte (6). The MRP2 protein is a member of the ABC transporter superfamily. The predicted topology of the MRP2 protein contains three MSD and two ABC (7). The ABC are functional regions responsible for nucleotide binding and have three motifs: Walker A, Walker B, and the signature C motif. These motifs are important for ATP binding and are highly conserved among members of the ABC transporter superfamily (7,8).The human ABCC2 gene is localized to chromosome 10q24, spans about 45 kb, and contains 32 exons (9). The first mutation of ABCC2 gene responsible for D...

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confidence: 99%

Neonatal Dubin-Johnson Syndrome: Long-Term Follow-up and MRP2 Mutations Study

Lee

Chen

et al. 2006

Pediatr Res

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“…Then, the lysosomes are transformed into the secondary ones [8] . Unlike in the Gilbert's syndrome, in DJS clinical manifestation of hepatomegaly can be found even in the neonatal-infantile period [3,7,[13][14] . In our patient, the cause of hyperbilirubinemia was unknown for many years.…”

Section: Discussionmentioning

confidence: 92%

Ultrastructure of Kupffer cells and hepatocytes in the Dubin-Johnson syndrome: A case report

Sobaniec-Łotowska

Lebensztejn²

2006

WJG

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Ultrastructure of Kupffer cells and hepatocytes in liver bioptate was evaluated in a 17-year-old boy with Dubin -Johnson syndrome (DJS). The liver tissue obtained by needle biopsy was fixed in glutaraldehyde and paraformaldehyde and routinely processed for electron microscopic analysis. The ultrastructural examinations of liver bioptate revealed the accumulation of membranebound, electron-dense lysosomal granules within the cytoplasm of hepatocytes, characteristic of DJS. They were located mainly in the vicinity of the biliary pole, and preferentially in the centrilobular region that corresponded to the pigment deposits seen under light microscope. The presence of the granules was accompanied by dilated elements of the granular endoplasmic reticulum and paracrystalline mitochondrial inclusions as well as dilation of the bile canaliculi. The changes in hepatocytes coexisted with marked stimulation and enhanced phagocytic activity of Kupffer cells. This was manifested in the accumulation of pigment deposits within their cytoplasm that corresponded to those observed in hepatocytes. Hyperactive pericentral Kupffer cells which are involved in the response to pigmentary material originating from disintegrated hepatocytes may play an essential role in the development of DJS.

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“…2 Our patient presented with jaundice in the neonatal period, which persisted for three months. Several cases of neonatal jaundice due to DJS have been reported in the international literature, 3,4 mostly with mild jaundice, but one case was reported to have severe cholestasis. 4 Usually DJS presents with recurrent jaundice in older children or adults.…”

Section: Case Reportmentioning

confidence: 99%

“…Several cases of neonatal jaundice due to DJS have been reported in the international literature, 3,4 mostly with mild jaundice, but one case was reported to have severe cholestasis. 4 Usually DJS presents with recurrent jaundice in older children or adults. These may be induced by surgery, intercurrent infections, vigorous physical exercise, or contraceptive pills.…”

Section: Case Reportmentioning

confidence: 99%